Abstract The goal of this Transformative R01 project is to develop genetic strategies for neuroengineering a robust vocal learning phenotype in mice, which may yield the first mammalian model for treating human vocal communication disorders. Up to 10% of humans have some sort of communication dysfunction in their lifetimes (Speech and Language Impairments, NICHCY, 2011), yet there is no genetically tractable system for enhancing or repairing brain circuits involved in speech. We recently discovered that mice, which are highly tractable, show evidence of a rudimentary vocal learning phenotype. Specifically, mice have some features once thought unique to humans and other vocal learning species, including the ability modify ultrasonic vocalizations (USVs) based on context; a forebrain vocal circuit that is active during vocalizing, is required for frequency modulation and organization of syllables, and that directly connects to brainstem motor neurons that control the larynx; and syllable sequencing deficits when given a FoxP2 mutation known to cause phoneme sequencing dyspraxia in humans. However, compared to humans and songbirds, these phenotypes are much more limited in mice. These and other findings led us to hypothesize that similar to natural variation in ability among vocal learners, presumed vocal non-learners may exhibit vocal learning-like phenotypes along a continuum of complexity across species. In this context, given the presence of the basic neuroarchitecture in mice considered obligate for vocal learning in categorical species, we postulate that the mouse vocal system and associated behaviors may be liable to enhancement, thereby providing a foundation for the development of novel and effective strategies for ameliorating disorders of human vocal communication. To accomplish this, we will exploit recent findings from our laboratory where we discovered convergent specialized gene expression of ~50 genes in vocal brain regions of several vocal learning species, including humans and songbirds, many of which are involved in brain pathway development. We hypothesize that evolutionary changes in the regulation of trait-specialized genes are responsible for the emergence of more advanced vocal plasticity and other complex behavioral traits. Our objective is to recapitulate the unique expression patterns of these genes in mice to enhance the vocal learning phenotype at the level of connectivity, in vivo electrophysiology, and behavior. We will do so using viral strategies, introduction of human neural stem cells, and the generation of transgenic animals. If successful, our studies are expected to impact the field by: 1) Establishing how vocal-learning specialized genes shape the neurocircuitry and physiology for this complex behavior; 2) Developing a novel, genetically tractable mammalian model system for unveiling the neurobiological details of human language and treatments for its dysfunction; and 3) Serving as a platform for neuroengineering complex behavioral traits in general.